PA-00-019 Mentored Research Scientist Development Award (K01) "Mechanisms of the Abeta sequestration in AD" The candidate, Yasuji Matsuoka, PhD, is a junior researcher with considerable experience in neuroscience research in Alzheimer's disease (AD). In order to become a fully independent translational neuroscientist in AD and other neurodegenerative diseases, an additional supervised training period is critical. The candidate is eager to expand his knowledge and techniques in both clinical and basic aspects of therapeutic research. Dr. Paul Aisen (Professor of Neurology and Medicine, and Director of the Memory Disorders Program at Georgetown University), will be the primary mentor for training in drug development for AD. Drs. Karen Gale (Professor of Pharmacology, Georgetown University) and Karen Duff (Associate Professor, Nathan Kline Institute / New York University) will be co-mentors to provide training in behavioral analysis using transgenic models of Alzheimer's disease. Additional consultants will provide expertise in basic research into neurodegeneration (Dr. Mattson), medicinal chemistry (Dr. Kozikowski) and neuroimaging (Dr. Fricke) Georgetown University Medical Center offers a stimulating scientific and clinical environment. The five year career development plan aims to: 1) provide the candidate a strong understanding and background in clinical drug development; 2) improve and extend his research experience and knowledge in behavioral analysis of AD mouse models; 3) assure ethical conduct in both clinical and basic research using human subjects and animals. The primary research goal of this proposal is the elucidation of a promising, novel therapeutic approach to AD, "Abeta sequestration". The candidate has demonstrated that brain Aa can be altered using non-immune amyloid-binding compounds. The research studies proposed will investigate the pools and conformations of Aa that can be influenced by peripheral binding compounds, the ideal structure of such compounds, and blood-brain barrier transport of Abeta.